Dmitry Shchelokov (1), Oleg Demin Jr (2)
(1) Lomonosov Moscow State University, Faculty of Biology, Moscow, Russia (2) InSysBio, Moscow, Russia
Introduction: Monoclonal antibodies (mAbs) are engineered immunoglobulins that have been used for several decades as therapeutic agents in immuno-oncology. Their protein nature and specific structure significantly influence pharmacokinetics (PK) behaviour. However, there is neither clear consensus nor guidance regarding how to model antibody biodistribution and choose the structure of empirical models for the better description of PK data. To address this issue, we developed a minimal physiologically based pharmacokinetic (PBPK) model of drug disposition and focused on a group of immune checkpoint inhibitors blocking the PD-1 receptor.
Objectives:
- To identify parameters of mAb uptake by endothelial cells on the basis of in vitro data
- To develop the PBPK model describing endogenous IgG biodistribution in healthy human
- To develop minimal PBPK model describing distribution of therapeutic mAbs and binding with PD-1 receptor
Methods: Computational model was presented in terms of ordinary differential equations (ODE) with reaction rates defined in accordance with mass action law. The model describes the main features of mAb disposition: intravenous administration, distribution within body fluids, fluid-phase uptake by endothelial cells, competition for neonatal Fc receptor (FcRn) binding with endogenous IgG in endosomal space, FcRn-dependent transcytosis and recycling by endothelial cells, degradation of unbound mAb within endothelial cells, convective and diffusive transfer across blood vessel wall, binding with PD-1 receptor expressed on the surface of T cells, internalization of mAb-PD-1 complex by T cells. Also, the model takes into account the valency of mAbs and describes surface binding of antigen and ternary complex formation [1]. The number of parameters was estimated on the basis of available published data, e.g., volumes of physiological compartments, blood and lymph flows, number of cells, levels of endogenous IgG in serum and lymph, etc [2]. To identify parameters related to antibody uptake, recycling, and degradation by endothelial cells, additional sub-model was developed and fitted against in vitro experimental data [3]. To select the values of the parameters we used the algorithm of fitting based on Hook-Jeeves method implemented in the DBSolve Optimum package which was used for the numerical solution of ODEs and visualization [4].
Results: Developed PBPK model was tested on a set of four anti-PD-1 monoclonal antibodies: nivolumab, pembrolizumab, MGA012, and TSR042. To this end, clinical findings were compared to model simulations performed under similar conditions (dose and schedule). Information on these therapeutics is available from the Food and Drug Administration biopharmaceutical reports or from ongoing clinical trials. Model adequately predicts the PK profile of all tested drugs, as well as target receptor occupancy in plasma and tumor, without any additional parameter fitting. The model shows 98% occupancy of PD-1 on T cells in tumor during treatment with an approved dose of nivolumab, whereas clinical data shows 85-97% PD-1 occupancy in the tumor [5]. It is important to note that no clinical data was used at the stage of the model calibration.
Conclusion: Pharmacokinetics of mAbs is presumably determined by their molecular size and structure (presence of Fc-domain), whereas antigen binding properties mostly affect target receptor occupancy and subsequent pharmacodynamic effect. However, more clinical data should be analyzed to test the predictive ability of the model. In conclusion, proposed minimal PBPK model offers an alternative approach to simulating pharmacokinetics of novel mAbs and may be used as a tool to select doses of antibodies for first-in-human studies.
References:
[1] Sengers BG, et al. Modeling bispecific monoclonal antibody interaction with two cell membrane targets indicates the importance of surface diffusion. MAbs. 2016 Jul;8(5):905-15.
[2] Basic anatomical and physiological data for use in radiological protection: reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89. Ann ICRP. 2002;32(3-4):5-265.
[3] Grevys A, et al. A human endothelial cell-based recycling assay for screening of FcRn targeted molecules. Nat Commun. 2018 Feb 12;9(1):621.
[4] Gizzatkulov NM, et al. DBSolve Optimum: a software package for kinetic modeling which allows dynamic visualization of simulation results. BMC Syst Biol. 2010 Aug 10;4:109.
[5] Das R, et al. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol. 2015 Feb 1;194(3):950-9.
Reference: PAGE 28 (2019) Abstr 8902 [www.page-meeting.org/?abstract=8902]
Poster: Drug/Disease Modelling - Absorption & PBPK